Prioritising research into age-related macular degeneration
As life expectancy increases, the number of people living with age-related macular degeneration (AMD) is set to rise dramatically, meaning it could become the next public health crisis. Existing treatments are of limited benefit, but researchers are exploring several avenues that could lead to new therapies.
Vision is, arguably, our most impressive sense. A healthy visual system can resolve a grating of 1cm lines from 34 metres away. Our eyes are sensitive to luminance varying from bright sunlight to darkness deeper than an overcast, moonless night; a range of intensities of 1010.1 Our eyes also convey social and emotional information that helps forge relationships.2
But age-related macular degeneration (AMD) threatens the sight of almost 700,000 people in the UK. The Macular Society predicts that AMD prevalence will double by 2050. “There are already far more people with macular disease than with dementia, with nearly 1.5 million people affected across the UK. AMD is the most common type of macular disease and, as we are living longer, the number of people living with the condition is set to increase dramatically,” says Cathy Yelf, Chief Executive of the Macular Society. “AMD is the next public health crisis.”
Ms Yelf adds that AMD already costs the UK at least £1.6 billion a year. “The NHS is unable to cope with the demand for AMD treatment,” she says. “Ophthalmology outpatient appointments have risen 30% in recent years. The drug costs alone for AMD are more than £200 million a year. Yet while drugs targeting vascular endothelial growth factor [VEGF] have had a considerable impact, it’s clear that they are not the solution to wet AMD. Meanwhile, there is no effective treatment for the most common form of the disease.” So, can we tackle this emerging public health crisis?
Directing the gaze
The eye directs the subject of our gaze onto the fovea – a 0.6mm diameter hollow in the retina. The ganglion cells (see Box 1) are displaced and blood vessels are absent. So, there’s little tissue to disrupt the light.1 The fovea lacks rods, but contains most of the retina’s five million cones, which are responsible for colour vision. Movements of the eyes keep the visual field clear.1
Box 1. An outgrowth of the brain
The macula is the area about 5.5mm in diameter that encompasses the fovea. Outside the macula, a decline in the number of photoreceptors and ganglion cells means that resolution about 6mm from the fovea is approximately a tenth of that in the centre.1 In addition, about half the primary visual cortex processes images from the macula at the expense of the rest of the retina. So, peripheral vision cannot compensate fully for damage to the macula.1
Some people with early AMD notice a mild distortion in their central vision, such as when reading in low light. However, early AMD is often asymptomatic.3 About half of people with late AMD show areas of damage to the retina (geographic atrophy), which tends to worsen over years or decades.3-5 The remainder have ‘wet’ AMD, when blood vessels proliferate behind the retina (choroidal neovascularisation), which typically progresses over weeks or months.3-5 As AMD progresses, patients typically experience distorted vision when reading, driving or watching television. They may have problems recognising faces and report a dark or grey patch (scotoma) in their central vision (see Figure 1). Not surprisingly, the visual loss caused by AMD seems to increase the risk of falls.3
“AMD brings fear and frustration, loss and loneliness,” says Ms Yelf. “Families are stretched trying to support relatives going through treatment or, even worse, experiencing irreversible loss of sight. Many people tell us that they are terrified of going blind and they allow their lives to be gripped by this fear.”
Figure 1. People with advanced age-related macular degeneration (AMD) may report a dark patch (scotoma) in their central vision
As we age, we become less efficient at removing waste material. Lipofuscin, for example, is a normal waste product formed in lysosomes (cell organelles rich in enzymes) that consists mainly of protein and lipid. Lysosomes fuse with the cell membrane and release their contents, which are then carried away and eliminated. This process becomes less efficient as you age, which is why some older people develop brown liver spots on their skin.6
In the eye, the retinal pigment epithelium (RPE) helps maintain, support and renew (through phagocytosis of fragments shed from rods and cones) the light-sensitive outer segments of photoreceptors.7 As we get older, intracellular granules containing lipofuscin accumulate in the RPE. The Bruch’s membrane – the collagenous layer under the RPE – thickens and becomes less permeable. And the RPE becomes less able to completely digest the outer segments of the photoreceptors, forming yellow, plaque-like, extracellular deposits called drusen between the RPE and the Bruch’s membrane.5
Small (<63µm diameter; also called hard) drusen are almost inevitable with normal ageing. However, medium-sized (63–125µm) or larger drusen, or macular hyper- or hypopigmentation, or both, characterise AMD.3 Drusen can also form elsewhere in the retina, although their clinical importance isn’t clear.3
Drusen consist of lipids, zinc and iron ions, and more than 129 proteins, including those involved in complement activation (see below) and beta-amyloid.3 Indeed, AMD shares several features with changes in the eyes of people with Alzheimer’s disease.8
In people with wet AMD (see Figure 2), increased production of VEGF promotes angiogenesis – the growth of new blood vessels – under the RPE and then the retina.5 These fragile blood vessels can leak, which further damages the retina,1 and form disc-like scars, which results in permanent visual loss.5
While researchers have sketched the outline of AMD’s pathogenesis, many details remain obscure. “Genetic and other studies suggest that there is more than one biochemical pathway that ultimately results in loss of vision through geographic atrophy, choroidal neovascularisation or a combination of these late-stage manifestations,” says Professor Paul Bishop from the University of Manchester and Manchester Royal Eye Hospital. “Recent studies show that there is a lot of cross over between geographic atrophy and choroidal neovascularisation. For example, patients with choroidal neovascularisation often have geographic atrophy.”
Figure 2. Wet age-related macular degeneration. Inset detail: photoreceptors are shown left (red and brown) with blood vessels behind them in the choroid layer. New, weak blood vessels grow and are prone to bleeding, preventing light from reaching the back of the eye. This can lead to a central dark patch in the patient’s vision and potential blindness
Studies are beginning to clarify the relative importance of the numerous genetic and environmental risk factors driving AMD. As the nosology denotes, almost all people with late AMD are older than 60 years of age.3 Indeed, about 10% of people aged between 66 and 74 years have AMD, increasing to 30% of those older than 75 years.1
Smoking is well-established as increasing the risk of developing late AMD – by between 1.8- and 3.0-fold and with a 10-year younger age of onset.3 “Colleagues in primary care should persuade patients to stop smoking. In addition, a healthy diet and lifestyle can reduce the risk of getting AMD,” adds Professor Bishop. “The advice is essentially the same as that we give to patients to reduce their risk of cardiovascular disease.”
Genes influence a person’s susceptibility to AMD when exposed to environmental factors. The siblings of a person with AMD, for instance, are between three and six times more likely to develop AMD than the general population.5 Indeed, genome-wide analysis of 16,144 patients and 17,832 controls linked 52 genetic variants at 34 loci (positions on the chromosome) with AMD.9 “Genetic changes can predispose to AMD to varying extent,” Professor Bishop says. “Patients with some rare genetic mutations are almost certain to get AMD if they have a normal lifespan. Other people may have some genetic risk but may not get AMD unless they have other risk factors, such as smoking.”
Indeed, researchers have linked numerous other risk factors with AMD, including exposure to sunlight, alcohol consumption, cataract surgery, cardiovascular disease, obesity, light iris colour and diabetes.3,5 In many cases, however, these links are tentative and await further investigation.3 Nevertheless, combining genetic analysis, patient demographics and the exposome (total environmental exposures) already allows ophthalmologists to characterise an individual’s risk of AMD progression10 with, Professor Bishop remarks, “a fairly good degree of accuracy”.
Such studies could stimulate research into new treatments; current pharmacological options are limited. Nevertheless, agents that block VEGF – introduced in the NHS in 2008 – have transformed the prospects for many people with wet AMD. “These drugs slow AMD in 90% of patients who are treated promptly and about 30% experience an improvement in their vision,” Ms Yelf says.
One study, for example, followed 96 patients, aged 76.5 years on average, in South West Scotland. Patients received a mean of 9.56 intravitreal injections of the anti-VEGF agent ranibizumab for wet AMD in a total of 104 eyes. During a mean follow-up of about 4.1 years, the mean visual loss was 5.5 letters with 24.0% of treated eyes losing at least 15 letters. However, 9.6% of treated eyes gained at least 15 letters. Moreover, the incidence of legal blindness due to wet AMD, standardised for age and sex, peaked at 9.1 per 100,000 of the population in 2006 declining to 4.8 per 100,000 in 2011.11 “Even so, many will still develop ‘low vision’ over time and for the 10% of people for whom anti-VEGF treatment does not work, the sight loss will be very significant,” Ms Yelf notes. “Most people need the treatment for life and there are now many patients who have had more than 70 injections.”
Currently, there is no approved treatment for dry AMD. However, supplements may help. The Age-Related Eye Disease Study (AREDS) randomised 3640 patients, aged 55–80 years, to receive: antioxidants (vitamin C 500mg, vitamin E 400IU and beta-carotene 15mg); zinc (zinc oxide 80mg and cupric oxide 2mg); antioxidants plus zinc; or placebo. After an average follow up of 6.3 years, antioxidants plus zinc significantly reduced the risk of developing advanced AMD by 28% compared with placebo. The 25% and 20% reductions for zinc alone and antioxidants alone respectively were not significant.12 Over five years, 1.3% of people with extensive small or non-extensive medium-sized drusen or pigment abnormalities developed advanced AMD. Excluding these low-risk patients, antioxidants plus zinc, zinc alone and antioxidants alone reduced progression by 34%, 29% and 24% respectively (the latter was not statistically significant).12
Nevertheless, experts are split about whether healthcare professionals should suggest that patients take supplements. “There are varying views on how to interpret this evidence,” Professor Bishop remarks. “My view is that the evidence is insufficient to recommend supplements to any groups of patients.” Professor Andrew Lotery, Chair, Scientific Committee, Royal College of Ophthalmologists, is more positive. “The AREDS study showed that high-dose vitamins reduced progression of moderate AMD to late-stage AMD by a quarter,” he says. “I think that hospital specialists should recommend supplements. Unfortunately, the NHS will no longer pay for them, so patients have to buy them over the counter.”
Researchers are exploring several avenues that could lead to new treatments, such as inflammation, which increasing evidence suggests drives AMD. Some studies, for instance, link raised levels of C-reactive protein (indicating systemic inflammation) with an increased risk of AMD. Drusen may trigger chronic inflammation,5 while polymorphisms (genetic variants) involved in the complement cascade (an important part of the adaptive and innate immune responses) can increase the risk of, or protect against, AMD.5
“There is very strong evidence that dysregulation of the complement system is important in AMD,” says Professor Bishop. “This system is there to protect against pathogens, but inadequately regulated complement can start attacking our own cells and tissues. There is a failure of regulation of the complement system in some forms of AMD. This can be a consequence of variations in certain genes within the complement system, such as complement factor H. The protein encoded by this gene is called factor H, which inhibits complement activation and so protects cells and tissues. Alterations to this gene make factor H less effective, thereby predisposing individuals to AMD.”
So, the complement system offers a tempting target for new AMD treatments. Tetracyclines, for example, may reduce the low-grade inflammation caused by the inadequately regulated complement pathway,5 although further studies are needed. Unfortunately, lampalizumab, an innovative treatment that inhibits complement, did not reduce the enlargement of geographic atrophy in phase 3 studies, despite showing promise in earlier studies. Detailed analysis – for instance, ascertaining any correlations between genotype and phenotype – may offer insights into AMD pathophysiology and the clinical development of future drugs.13
Despite this setback, the complement system seems to remain the best prospect for a new treatment. “Current evidence suggests that targeting the complement pathway is most likely to yield new treatments for AMD, especially for geographic atrophy,” says Professor Bishop. “The genetic studies have identified possible drug targets, particularly inhibition of the complement pathway,” Professor Lotery adds. “Clinical trials are underway to see if this could result in a new therapy.”
In addition, some studies suggest that high-dose statins may regress drusen, which, after all, are rich in lipids.3,5 Glatiramer acetate, which suppress T lymphocytes and downregulates inflammatory cytokines,5 appears to dampen inflammation and is already used as a disease-modifying treatment for multiple sclerosis. Again, additional studies are needed.
More experimental approaches target inflammasomes (intracellular complexes that detect pathogens and stimulate immune responses) or modulate the translation of photons hitting rods or cones into an electrical signal in the retina (visual cycle). Gene therapies could increase expression of anti-angiogenic proteins, which may reduce the need for intravitreal injections. Stem cell treatments raise the prospect of replacing dead or dysfunctional retinal pigment epithelium with healthy tissue.3,5
Despite these promising approaches, fundamental questions remain, Professor Lotery notes, such as why early AMD progresses to the later sight-threatening forms. “We have some insights into the biochemical and cellular pathways that drive AMD pathogenesis, but our knowledge is far from complete,” Professor Bishop adds. “This question can be addressed, at least in part, by trying to understand the downstream biochemical consequences of the genetic variations that predispose to AMD. This is the main focus of work in my laboratory, as we think that understanding this will allow the development of new therapeutics.”
Yet despite being a devastating disease, a paucity of funds could stifle innovation. “Of the £3 billion of public money spent on medical research in 2014, only £22.7 million was spent on eye disease. Of that, only £6 million was spent on AMD, the biggest cause of sight loss,” Ms Yelf notes. “Charities in the sight-loss sector raised nearly three-quarters of a billion pounds in 2014, but gave only £1.5 million to AMD research. Yet many researchers say they believe a solution to AMD is possible.” In response, the Macular Society plans to fund £6 million of research annually over the next five years.
In the meantime…
In the meantime, management depends on monitoring patients for visual changes and wet AMD. Spectral domain optical coherence tomography (SD-OCT), for instance, detects the vascular networks characteristic of choroidal neovascularisation. “SD-OCT has become essential to managing AMD and is performed during virtually every outpatient visit,” Professor Lotery says. “SD-OCT has identified features that detect faster progression of the disease, such as extracellular deposits above the RPE called reticular pseudodrusen.”
So, healthcare professionals should encourage patients to attend their eye tests. “In addition, any elderly patient who complains of reduced vision or blurred, distorted central vision may have wet AMD. This requires urgent assessment as early treatment is much more effective in preventing sight loss,” Professor Lotery advises.
“There is, however, a pressing need for further investment in eye clinics, so that the little treatment that is available can be given in a timely way,” Ms Yelf concludes. “Thousands of people are losing more vision than they should because they are undertreated as a result of the lack of capacity in eye clinics. It is a tragedy that people lose sight when there is a treatment that will help keep their vision for longer, but it is not given in time.”
Declaration of interests
Mark Greener is a full-time medical writer and, as such, regularly provides editorial and consultancy services to numerous pharmaceutical, biotechnology and device companies and their agencies. He has no shares or financial interests relevant to this article.
Mark Greener is a freelance medical writer
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